On her return to South Africa, Nkoana-Mashabane became Limpopo's Local Government and Housing Member of the Executive Council, winning a wide following in the province for her efforts to root out corruption in low-cost housing programmes and her hands-on approach to rural housing.

In December 2012, Nkoana-Mashabane was re-elected as a member of the National Executive Committee of the ruling party at the party's 53rd National Conference, held in Mangaung, Free State Province. Her first election to the NEC was at the party's December 2007 National Conference, held in the city of Polokwane.

President Jacob Zuma appointed Nkoana-Mashabane as Minister of International Relations and Cooperation on 9 May 2009. Zuma subsequently disputed suggestions that this was an unusual appointment in light of Nkoana-Mashabane's apparent lack of foreign policy experience, saying that "the ANC knows the strengths of this comrade" and noting that she was a member of the ANC National Executive Committee.[2]

During Nkoana-Mashabane's tenure as Minister of International Relations and Cooperation, South Africa became a member of the group of emerging economies under the BRICS (Brazil, Russia, India, China, South Africa) banner. Nkoana-Mashabane was President of the 2011 United Nations Climate Change Conference held in Durban from 28 November to 11 December 2011.[3]